US5756492A - Graft survival prolongation with porphyrins - Google Patents

Graft survival prolongation with porphyrins Download PDF

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US5756492A
US5756492A US08/709,650 US70965096A US5756492A US 5756492 A US5756492 A US 5756492A US 70965096 A US70965096 A US 70965096A US 5756492 A US5756492 A US 5756492A
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transplant
metalloprotoporphyrin
organ
recipient
survival
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Roland Buelow
Jacky Woo
Suhasini Iyer
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Sangstat Medical Corp
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Priority to EP97909836A priority patent/EP0865275A2/en
Priority to PCT/US1997/015572 priority patent/WO1998009618A2/en
Priority to AU47344/97A priority patent/AU740531B2/en
Priority to CA002234886A priority patent/CA2234886A1/en
Priority to JP51289398A priority patent/JP3287851B2/en
Priority to ZA9707960A priority patent/ZA977960B/en
Priority to ARP970104091A priority patent/AR009560A1/en
Priority to US09/045,562 priority patent/US6060467A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the inflammatory process is an extraordinarily complex process, varying with the cause of inflammation, the site of the inflammation, and the nature of the insult. Numerous different types of leukocytes are attracted to the site where the inflammatory process is initiated. The different leukocytes initiate different biological processes to respond to the insult. While in many situations, the inflammatory response is healthy in destroying a pathogen, in other situations, such as autoimmune diseases and transplantation, the inflammatory response is undesirable. In the latter case, this leads to rejection and loss of the implanted organ, which in most cases will be fatal.
  • xenografts Because of the restricted availability of donor organs, consideration has been given to using xenografts for temporary maintenance, while an acceptable allogenic organ is identified.
  • the xenografts not only differ as to the MHC, but will also have numerous other epitopes differing from the host. Therefore, additional rejection mechanisms are brought to bear against the xenograft.
  • Heme oxygenase has been the subject of numerous studies as evidenced by the review article, Abraham et al., Int. J. Biochem. (1988) 20(6):543-558. Recently, modulation of heme oxygenase activity has been described in Raju and Maines, Biochimica et Biophysica Acta (1994) 1217:273-280; Neil et al. J. of Ocular Pharmacology and Therapeutics (1995) 11(3):455-468; Haga et al., ibid. (1996) 1316:29-34; Willis et al., Nature Medicine (1996) 2(l):87-90; and Agarwal et al., Transplantation (1996) 61(1):93-98.
  • Transplant survival in mammalian hosts is enhanced by providing a therapeutic dose of a metallic protoporphyrin in conjunction with the transplantation.
  • inhibitory metallic protoporphyrins are employed in an amount sufficient to inhibit heme oxygenase at a time proximal to the time of transplant, whereby the survival of the transplant is extended.
  • FIG. 1 is a graph of the inhibition of target cell lysis by metalloprotoporphyrins. T-cell mediated cell lysis was evaluated in the presence of varying amounts of Zn- and Co-protoporphyrin in a four hour chromium release assay;
  • FIG. 2 is a graph showing the prolongation of heart allograft survival following metalloprotoporphyrin therapy.
  • Methods are provided for prolonging the acceptance of transplants in a mammalian host.
  • the method employs the administration of a metalloprotoporphyrin prior to concomitant with, subsequent to or a combination thereof with the transplant.
  • a particular regimen is employed for administration, where a single bolus or plurality of doses may be administered to the recipient and/or donor, before, concomitant with, or subsequent to the implanting of the organ in the recipient.
  • the particular protocol will depend upon the nature of the organ, the particular metalloprotoporphyrin which is employed, and the use of other immunosuppressants.
  • Adminstration will usually begin within 7 days prior to the transplant, preferably within about 3 days, and desirably will include the day prior to the transplant and particularly, the same day as and/or the day after the transplantion. Administration may be on consecutive days or non-consecutive days, generally any gap being fewer than 10 days. Adminstration concomitant with the transplant or on the same day may be useful, but preferably in most instances administration will begin on the first day after the transplant and may be continued until the transplant is stabilized, generally not exceeding one month, more usually not exceeding two weeks.
  • the metalloprotoporphyrin may also be administered to the donor, usually within three days of the removal of the organ, more usually not later than the day prior to removal of the organ, desirably within about 12 hours of the removal of the organ.
  • the metalloprotoporphyrins of interest in this invention include iron, cobalt, tin, zinc, and manganese, particularly cobalt and zinc.
  • the subject compounds may be formulated in a variety of ways, depending upon the nature of administration, the particular metalloprotoporphyrin, the number of administrations, other drugs, and the like. Therefore, the administration may vary with whether the donor, recipient or organ is being treated, the number of administrations, the manner of administration, the presence of other active components, and the like.
  • the formulation will generally be in a physiologically acceptable form, using various carriers, such as water, deionized water, phosphate buffered saline, aqueous ethanol, vegetable oils, etc.
  • the formulation may be formulated as a slow release formulation, where the subject compounds may be encapsulated in a wide variety of carriers, may be administered as capsules, or as a prodrug.
  • the subject compounds may be taken parenterally or orally, generally being administered intravascularly, subcutaneously, or intramuscularly. Depending upon the manner of administration, and the frequency of administration, the dosage will generally be in the range of about 0.5 to 50 mg/kg.
  • conventional medium such as organ preservation solution.
  • the temperature at which the organ may be maintained will be conventional, generally in the range of about 1° C. to 8° C.
  • the residence time of the organ in the medium will generally be in the range of about 2 to 48 h, more usually 2 to 24 h.
  • the total amount of the subject compound per day will generally be in the range of about 0.5 to 50, more usually in the range of about 1 to 25 mg/kg/day.
  • This dose may be in a single bolus or be divided up to be administered in portions to provide the desired level of the subject compound in the host.
  • the subject compositions may be used with a wide variety of hosts, particularly primates, more particularly humans, or with domestic animals, and the like.
  • the subject compositions may be used in conjunction with the transplantation of a wide variety of organs, such as kidney, heart, liver, spleen, bone marrow, pancreas, lung, islet of langerhans, etc.
  • compositions may be used as adjunctive therapy with immunosuppresssant compounds, such as cyclosporine, FK506, MHC Class I oligopeptides, or other immunosuppressants, where reduced amounts of the immunosuppressant may be used, generally reducing the amount employed by at least 25%, more usually at least 40% or more, from the therapeutic dosage for the indication.
  • immunosuppresssant compounds such as cyclosporine, FK506, MHC Class I oligopeptides, or other immunosuppressants, where reduced amounts of the immunosuppressant may be used, generally reducing the amount employed by at least 25%, more usually at least 40% or more, from the therapeutic dosage for the indication.
  • the graft life will be extended for at least three days beyond what could normally be anticipated in the absence of the subject compound, more usually at least five days. This can be useful in areas where xenogeneic grafts have been used awaiting an allogenic graft, to allow for reduced amounts of immunosuppressants or avoid using immunosuppressants altogether.
  • the subject compounds may be used for allogenic, as well as xenogenic, grafts.
  • mice Male, 7-8 week old CBA/J (H-2 k ) and C57BL/6/J (H-2 b ) mice were purchased from the Jackson Laboratory (Bar Harbor, Me.). Mice were maintained in our animal facility following Animal Welfare Guideline, Department of Health, CA.
  • Synthetic Metalloporphyrins Various synthetic metalloporphyrins were purchased from Porphyrin Products, Inc. (Logan, Utah). They were dissolved in 0.2M NaOH, adjusted to pH 74. with 1M HCl and subsequently diluted to 1 mg/ml in PBS.
  • Cytotoxic T-cell Activity To assay the effect of metalloprotoporphyrins on cytotoxic T-cell activity, CBA to B6 effectors were generated following a five day culture of 3 ⁇ 10 6 CBA spleen cells with 3 ⁇ 10 6 mitomycin-treated B6 spleen cells in wells of a 24-well plate (Nunclone Delta, Nunc, Denmark) in R-10 medium. Effector cells were then harvested and washed. (H2b), a mouse lymphoma induced in C57BL/6N was used as target cells. EL4 cells were routinely subcultured once every three days.
  • Heterotopic Heart Transplantation Abdominal heterotopic heart transplantation was performed as previously described by Ono and Lindsey (J. thorac. Cardiovasc. Surg. 1969 7:225-229) using C56B1/6 donors and CBA recipients. Metalloporphyrin was administered intraperitoneally using various protocols. Heart allograft survival was monitored daily by direct palption, and rejection was defined as termination of palpable cardiac contractility. Results are expressed as percentage graft survival at a given postoperative period. Statistical analysis was performed with the Mann-Whitney test.
  • Zinc- and cobalt-protoporphyrin inhibit cytotoxicity in vitro.
  • the effect of Zn- and Co-protoporphyrins on T- and NK-cell mediated cytotoxicity was evaluated in an in vitro four hour chromium release assay. Results of a representative experiment using cytotoxic T-cells are shown in FIG. 1. Similar results were observed in NK-cell assays.
  • Addition, of protoporphyrin to the tissue culture inhibited target cell lysis in a dose dependent manner. At about 10 ⁇ g/ml target cell lysis was inhibited completely (0% lysis). At even higher concentrations, chromium release from target cells in the presence of protoporphyrins was lower than the spontaneous release observed in the absence of the compounds.
  • Zinc- and cobalt-protoporphyrin therapy of heart allograft recipients results in prolongation of graft survival.
  • the effect of metalloprotoporphyrins therapy on heart allograft survival was evaluated in a mouse model.
  • CBA recipients of C57B1/6 hearts were treated following transplantation with several doses of Zn- or co-protoporphyrin.

Abstract

Metalloporphyrins are administered in conjunction with transplantation to enhance the survival of the organ.

Description

BACKGROUND
The inflammatory process is an extraordinarily complex process, varying with the cause of inflammation, the site of the inflammation, and the nature of the insult. Numerous different types of leukocytes are attracted to the site where the inflammatory process is initiated. The different leukocytes initiate different biological processes to respond to the insult. While in many situations, the inflammatory response is healthy in destroying a pathogen, in other situations, such as autoimmune diseases and transplantation, the inflammatory response is undesirable. In the latter case, this leads to rejection and loss of the implanted organ, which in most cases will be fatal.
A number of different avenues have been investigated to encourage the retention of allografts. For the most part, these avenues have involved general immunosuppression, using drugs such as cyclosporin and FK 506. Extensive efforts have been directed to inducing anergy toward the foreign tissue. Also, the role of various factors has been investigated, where by modulating the level of the factors, the immune response may be diminished. For the most part, the primary approach has been the use of drugs which suppress the entire immune system, therefore leaving the patient vulnerable to adventitious infection.
Because of the restricted availability of donor organs, consideration has been given to using xenografts for temporary maintenance, while an acceptable allogenic organ is identified. The xenografts not only differ as to the MHC, but will also have numerous other epitopes differing from the host. Therefore, additional rejection mechanisms are brought to bear against the xenograft.
There is a pressing need to find alternative modalities which provide protection against transplant rejection. These modalities may find use in conjunction with other drugs, where lower levels of other drugs having significant side effects may be used effectively, so as to reduce the detrimental side effects. Thus, there is substantial interest in developing new approaches to reducing the rejection phenomenon, where the drug may act by itself or in conjunction with other drugs.
BRIEF DESCRIPTION OF THE RELEVANT LITERATURE
Heme oxygenase has been the subject of numerous studies as evidenced by the review article, Abraham et al., Int. J. Biochem. (1988) 20(6):543-558. Recently, modulation of heme oxygenase activity has been described in Raju and Maines, Biochimica et Biophysica Acta (1994) 1217:273-280; Neil et al. J. of Ocular Pharmacology and Therapeutics (1995) 11(3):455-468; Haga et al., ibid. (1996) 1316:29-34; Willis et al., Nature Medicine (1996) 2(l):87-90; and Agarwal et al., Transplantation (1996) 61(1):93-98.
SUMMARY OF THE INVENTION
Transplant survival in mammalian hosts is enhanced by providing a therapeutic dose of a metallic protoporphyrin in conjunction with the transplantation. Specifically, inhibitory metallic protoporphyrins are employed in an amount sufficient to inhibit heme oxygenase at a time proximal to the time of transplant, whereby the survival of the transplant is extended.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of the inhibition of target cell lysis by metalloprotoporphyrins. T-cell mediated cell lysis was evaluated in the presence of varying amounts of Zn- and Co-protoporphyrin in a four hour chromium release assay;
FIG. 2 is a graph showing the prolongation of heart allograft survival following metalloprotoporphyrin therapy. CBA recipients of C57B1/6 heart allografts were either untreated or treated as follows: ZnPP group (n=4); Zn-protoporphyrin was administered at 10 mg/kg/day on day -1 before transplantation and on days 1-9 post transplantation. CoPP group (n=4); Co-protoporphyrin was administered at 20 mg/kg/day on days 0-5 post-transplantation; ZnPP pretreatment group (n=3); heart donors were treated one day before transplantation with 50 mg/kg Zn-protoporphyrin.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Methods are provided for prolonging the acceptance of transplants in a mammalian host. The method employs the administration of a metalloprotoporphyrin prior to concomitant with, subsequent to or a combination thereof with the transplant. A particular regimen is employed for administration, where a single bolus or plurality of doses may be administered to the recipient and/or donor, before, concomitant with, or subsequent to the implanting of the organ in the recipient. The particular protocol will depend upon the nature of the organ, the particular metalloprotoporphyrin which is employed, and the use of other immunosuppressants.
Adminstration will usually begin within 7 days prior to the transplant, preferably within about 3 days, and desirably will include the day prior to the transplant and particularly, the same day as and/or the day after the transplantion. Administration may be on consecutive days or non-consecutive days, generally any gap being fewer than 10 days. Adminstration concomitant with the transplant or on the same day may be useful, but preferably in most instances administration will begin on the first day after the transplant and may be continued until the transplant is stabilized, generally not exceeding one month, more usually not exceeding two weeks. The metalloprotoporphyrin may also be administered to the donor, usually within three days of the removal of the organ, more usually not later than the day prior to removal of the organ, desirably within about 12 hours of the removal of the organ.
A number of different metalloprotoporphyrins are known, which have been used for the inhibition of heme oxygenase. Depending upon the nature of the particular metal which is chelated by the protoporphyrin, and the protocol employed, either induction or inhibition of the heme oxygenase is observed. Contradictory reports exist in the literature as to the effect of the particular metal. Abraham et al., Int. J. Biochem. (1988) 20(6):543-558 report that tin, cobalt, zinc and manganese act as competitive inhibitors of the enzyme, while Neil et al., J. of Ocular Pharmacology and Therapeutics (1995) 11(3):455-468, and Maines, Biochim. et Biophys. Acta (1981) 673:339-350 concur that zinc and tin inhibit, but indicate that cobalt induces activity. Therefore, the role of the metalloporphyrins in the prolongation of the survival of the graft will be associated with the modulation of heme oxygenase I activity.
The metalloprotoporphyrins of interest in this invention include iron, cobalt, tin, zinc, and manganese, particularly cobalt and zinc.
The subject compounds may be formulated in a variety of ways, depending upon the nature of administration, the particular metalloprotoporphyrin, the number of administrations, other drugs, and the like. Therefore, the administration may vary with whether the donor, recipient or organ is being treated, the number of administrations, the manner of administration, the presence of other active components, and the like. The formulation will generally be in a physiologically acceptable form, using various carriers, such as water, deionized water, phosphate buffered saline, aqueous ethanol, vegetable oils, etc. In some instances, the formulation may be formulated as a slow release formulation, where the subject compounds may be encapsulated in a wide variety of carriers, may be administered as capsules, or as a prodrug. The subject compounds may be taken parenterally or orally, generally being administered intravascularly, subcutaneously, or intramuscularly. Depending upon the manner of administration, and the frequency of administration, the dosage will generally be in the range of about 0.5 to 50 mg/kg.
When bathing the organ in a composition comprising the subject compound, conventional medium may be used, such as organ preservation solution. The temperature at which the organ may be maintained will be conventional, generally in the range of about 1° C. to 8° C. The residence time of the organ in the medium will generally be in the range of about 2 to 48 h, more usually 2 to 24 h.
When administered parenterally, generally the total amount of the subject compound per day will generally be in the range of about 0.5 to 50, more usually in the range of about 1 to 25 mg/kg/day. This dose may be in a single bolus or be divided up to be administered in portions to provide the desired level of the subject compound in the host.
The subject compositions may be used with a wide variety of hosts, particularly primates, more particularly humans, or with domestic animals, and the like. The subject compositions may be used in conjunction with the transplantation of a wide variety of organs, such as kidney, heart, liver, spleen, bone marrow, pancreas, lung, islet of langerhans, etc.
The subject compositions may be used as adjunctive therapy with immunosuppresssant compounds, such as cyclosporine, FK506, MHC Class I oligopeptides, or other immunosuppressants, where reduced amounts of the immunosuppressant may be used, generally reducing the amount employed by at least 25%, more usually at least 40% or more, from the therapeutic dosage for the indication.
Generally, the graft life will be extended for at least three days beyond what could normally be anticipated in the absence of the subject compound, more usually at least five days. This can be useful in areas where xenogeneic grafts have been used awaiting an allogenic graft, to allow for reduced amounts of immunosuppressants or avoid using immunosuppressants altogether.
The subject compounds may be used for allogenic, as well as xenogenic, grafts.
EXPERIMENTAL
The following examples are offered by illustration and not by way of limitation.
Materials and Methods
Animals: Male, 7-8 week old CBA/J (H-2k) and C57BL/6/J (H-2b) mice were purchased from the Jackson Laboratory (Bar Harbor, Me.). Mice were maintained in our animal facility following Animal Welfare Guideline, Department of Health, CA.
Synthetic Metalloporphyrins: Various synthetic metalloporphyrins were purchased from Porphyrin Products, Inc. (Logan, Utah). They were dissolved in 0.2M NaOH, adjusted to pH 74. with 1M HCl and subsequently diluted to 1 mg/ml in PBS.
Cytotoxic T-cell Activity: To assay the effect of metalloprotoporphyrins on cytotoxic T-cell activity, CBA to B6 effectors were generated following a five day culture of 3×106 CBA spleen cells with 3×106 mitomycin-treated B6 spleen cells in wells of a 24-well plate (Nunclone Delta, Nunc, Denmark) in R-10 medium. Effector cells were then harvested and washed. (H2b), a mouse lymphoma induced in C57BL/6N was used as target cells. EL4 cells were routinely subcultured once every three days. They were then collected, washed, and labeled with 0.1 mCi of sodium chromate-51 in 200 μl for one hour at 37° C. Effector (E) and target (t) cells were added into V-shaped tissue culture plates (Nunc, Denmark) at E:T of 20:1. Metalloprotoporphyrins were diluted to the working concentrations with PBS and added at the beginning of the four hour incubation period. For the determination of maximal release, 1% triton X-100 was added to separate wells. Plates were centrifuged for three minutes to increase cellular contact before the four hour incubation period. After incubation 75 μl supernatant from each well was collected and the amount of 51 Cr released was counted using a TopCount scintillation counter. The degree of cell lysis was calculated using the formula below: ##EQU1##
Heterotopic Heart Transplantation: Abdominal heterotopic heart transplantation was performed as previously described by Ono and Lindsey (J. thorac. Cardiovasc. Surg. 1969 7:225-229) using C56B1/6 donors and CBA recipients. Metalloporphyrin was administered intraperitoneally using various protocols. Heart allograft survival was monitored daily by direct palption, and rejection was defined as termination of palpable cardiac contractility. Results are expressed as percentage graft survival at a given postoperative period. Statistical analysis was performed with the Mann-Whitney test.
Results
Zinc- and cobalt-protoporphyrin inhibit cytotoxicity in vitro. The effect of Zn- and Co-protoporphyrins on T- and NK-cell mediated cytotoxicity was evaluated in an in vitro four hour chromium release assay. Results of a representative experiment using cytotoxic T-cells are shown in FIG. 1. Similar results were observed in NK-cell assays. Addition, of protoporphyrin to the tissue culture inhibited target cell lysis in a dose dependent manner. At about 10 μg/ml target cell lysis was inhibited completely (0% lysis). At even higher concentrations, chromium release from target cells in the presence of protoporphyrins was lower than the spontaneous release observed in the absence of the compounds. These results demonstrate modulation of HO activity by metalloporphyrins results in inhibition of cytotoxicity in vitro.
Zinc- and cobalt-protoporphyrin therapy of heart allograft recipients results in prolongation of graft survival. The effect of metalloprotoporphyrins therapy on heart allograft survival was evaluated in a mouse model. CBA recipients of C57B1/6 hearts were treated following transplantation with several doses of Zn- or co-protoporphyrin. Compared to control animals (mean survival time=7.8±1.1) heart allograft survival was significantly prolonged to 12.0±2.4 (p=0.008) and 10.5±0.6 (p=0.004) days in Zn- or Co-protoporphyrin treated animals, respectively. Pre-treatment of heart donors one day before transplantation resulted in a prolongation of graft survival to 10.3±1.5 days (p=0.03).
It is evident from the above results, that by using metalloprotoporphyrins, one can greatly extend the survival of implants in a host. The compounds have few side effects and can be used safely with positive results.
All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

Claims (13)

What is claimed is:
1. A method for extending the survival of an organ transplant in a recipient, said method comprising:
contacting said organ transplant with a metalloprotoporphyrin in an amount sufficient to extend the survival time of said transplant.
2. A method according to claim 1, wherein said contacting is ex vivo.
3. A method according to claim 1, wherein the step of contacting comprises contacting said organ transplant with said metalloprotoporphyrin on day one subsequent to the transplantation of said organ in said recipient.
4. A method according to claim 3, wherein the step of contacting comprises contacting said organ transplant with multiple dosages of said metalloprotoporphyrin within a period of two weeks.
5. A method according to claim 3 further comprising administering said metalloprotoporphyrin prior to transplant of said organ.
6. A method according to claim 1, wherein the step of contacting comprises administering said metalloprotoporphyrin to the donor of said organ prior to removal of said organ from said donor.
7. A method for extending the survival of an organ transplant in a recipient, said method comprising:
administering parenterally to the recipient of said organ transplant at least one of a cobalt or zinc metalloprotoporphyrin in an amount sufficient to extend the survival time of said transplant, said step of administering comprising administering to said recipient said at least one of said cobalt or zinc metalloprotoporphyrin at least on day one after the transplant.
8. A method according to claim 7, wherein the step of administering comprises administering to said recipient repeated dosages during a period of two weeks after said transplant.
9. A method according to claim 8, wherein said transplant is an allograft.
10. A method according to claim 9, wherein said allograft is a heart.
11. A method according to claim 8, wherein said metalloprotoporphyrin is zinc metalloprotoporphyrin.
12. A method according to claim 8, wherein said metalloprotoporphyrin is cobalt metalloprotoporphyrin.
13. A method for extending the survival of an organ transplant in a recipient, said method comprising:
contacting said organ transplant with a compound capable of modulating heme oxygenase I activity in an amount sufficient to extend the survival time of said transplant.
US08/709,650 1996-09-09 1996-09-09 Graft survival prolongation with porphyrins Expired - Fee Related US5756492A (en)

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Application Number Priority Date Filing Date Title
US08/709,650 US5756492A (en) 1996-09-09 1996-09-09 Graft survival prolongation with porphyrins
EP97909836A EP0865275A2 (en) 1996-09-09 1997-09-03 Graft survival prolongation with porphyrins
PCT/US1997/015572 WO1998009618A2 (en) 1996-09-09 1997-09-03 Graft survival prolongation with porphyrins
AU47344/97A AU740531B2 (en) 1996-09-09 1997-09-03 Graft survival prolongation with porphyrins
CA002234886A CA2234886A1 (en) 1996-09-09 1997-09-03 Graft survival prolongation with porphyrins
JP51289398A JP3287851B2 (en) 1996-09-09 1997-09-03 Porphyrin prolongs graft survival
ZA9707960A ZA977960B (en) 1996-09-09 1997-09-04 Graft survival prolongation with porphyrins.
ARP970104091A AR009560A1 (en) 1996-09-09 1997-09-08 PROLONGATION OF THE SURVIVAL OF GRAFT WITH PORPHYRINS
US09/045,562 US6060467A (en) 1996-09-09 1998-03-20 Graft survival prolongation with porphyrins

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6346547B1 (en) 1999-02-08 2002-02-12 Checkpoint, Genetics, Inc. N-substituted amino acids, antioxidant pharmaceutical compositions containing n-substituted amino acids and methods for preventing cardiovascular diseases and/or preventing and/or treating antioxidant responsive diseases therewith
WO2003051347A1 (en) * 2001-12-19 2003-06-26 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Use of urokinase receptor antagonists to modulate ischemiareperfusion injury
US20040131602A1 (en) * 1998-12-17 2004-07-08 Roland Buelow Methods for enhancing graft survival by modulating heme oxygenase activity
US20040143025A1 (en) * 2002-04-01 2004-07-22 Roland Buelow Carbon monoxide generating compunds for treatment of vascular, inflammatory and immune disorders
EP1499186A1 (en) * 2002-04-15 2005-01-26 Beth Israel Deaconess Medical Center Use of heme oxygenase-1 and products of heme degradation
US20060115542A1 (en) * 2001-05-15 2006-06-01 Motterlini Roberto A Therapeutic delivery of carbon monoxide
US20060127501A1 (en) * 2002-11-20 2006-06-15 Motterlini Roberto A Therapeutic delivery of carbon monoxide to extracorporeal and isolated organs
US20060233890A1 (en) * 2002-02-04 2006-10-19 Alfama - Investigacao E Desenvolvimento De Produtos Farmaceuticos Lda Method for treating a mammal by administration of a compound having the ability to release CO
US20070207217A1 (en) * 2003-02-03 2007-09-06 Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda Method for treating a mammal by administration of a compound having the ability to release CO
US20070219120A1 (en) * 2002-02-04 2007-09-20 Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda Methods for treating inflammatory disease by administering aldehydes and derivatives thereof
US20080026984A1 (en) * 2002-02-04 2008-01-31 Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda Methods for treating inflammatory disease by administering aldehydes and derivatives thereof
US20080160636A1 (en) * 2000-03-24 2008-07-03 Duke University Isolated GRP94 ligand binding domain polypeptide and nucleic acid encoding same, and screening methods employing same
US20090149436A1 (en) * 2004-11-16 2009-06-11 Astellas Pharma Inc. Caspase inhibitor
US8389572B2 (en) 2006-01-24 2013-03-05 Hemocorm Limited Therapeutic delivery of carbon monoxide
US9062089B2 (en) 2011-07-21 2015-06-23 Alfama, Inc. Ruthenium carbon monoxide releasing molecules and uses thereof
US9163044B2 (en) 2011-04-19 2015-10-20 Alfama, Inc. Carbon monoxide releasing molecules and uses thereof
US9314443B2 (en) 2011-10-12 2016-04-19 National Center For Child Health And Development Enhancer of survival of transplanted organ
US9399029B2 (en) 2012-07-13 2016-07-26 Sbi Pharmaceuticals Co., Ltd. Immune tolerance inducer
WO2018144845A1 (en) * 2017-02-03 2018-08-09 The Board Of Trustees Of The Leland Stanford Junior University Metalloporphyrin microparticles for treatment of anemia and tropical diseases
WO2023287665A1 (en) * 2021-07-12 2023-01-19 Renibus Therapeutics, Inc. Metal protoporphyrin for treatment of bk virus

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6127356A (en) 1993-10-15 2000-10-03 Duke University Oxidant scavengers
IL135949A0 (en) 1997-11-03 2001-05-20 Univ Duke Substituted porphyrins
ATE312103T1 (en) 1999-01-25 2005-12-15 Nat Jewish Med & Res Center SUBSTITUTED PORPHYRINS AND THEIR THERAPEUTIC USES
US20030069281A1 (en) * 2000-06-14 2003-04-10 Irwin Fridovich Tetrapyrroles
WO2002060383A2 (en) 2001-01-19 2002-08-08 National Jewish Medical And Research Center Cancer therapy
JP2005508864A (en) * 2001-06-01 2005-04-07 ナショナル・ジュウィッシュ・メディカル・アンド・リサーチ・センター Oxidant scavengers for the treatment of diabetes or for use in transplantation or for induction of immune tolerance
US7485721B2 (en) * 2002-06-07 2009-02-03 Duke University Substituted porphyrins
GB2397067B (en) * 2002-12-23 2005-05-11 Destiny Pharma Ltd Porphin & azaporphin derivatives with at least one cationic-nitrogen-containing meso-substituent for use in photodynamic therapy & in vitro sterilisation
GB2415372A (en) 2004-06-23 2005-12-28 Destiny Pharma Ltd Non photodynamical or sonodynamical antimicrobial use of porphyrins and azaporphyrins containing at least one cationic-nitrogen-containing substituent
EP1762248A1 (en) * 2005-09-09 2007-03-14 CORIT Consorzio per la Ricerca sul Use of cobalt porphyrins in joint therapy with an immunosuppressant drug for treatment of transplant patients or autoimmune disorders
JP5608644B2 (en) 2008-05-23 2014-10-15 ナショナル ジューイッシュ ヘルス Methods for treating damage associated with exposure to alkylated species

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4829984A (en) * 1983-12-15 1989-05-16 Gordon Robert T Method for the improvement of transplantation techniques and for the preservation of tissue
US5563132A (en) * 1994-06-21 1996-10-08 Bodaness; Richard S. Two-step cancer treatment method

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2132690A1 (en) * 1994-09-22 1996-03-23 Dean Willis Control and modulation of inflammatory response in humans in need of such control and modulation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4829984A (en) * 1983-12-15 1989-05-16 Gordon Robert T Method for the improvement of transplantation techniques and for the preservation of tissue
US5563132A (en) * 1994-06-21 1996-10-08 Bodaness; Richard S. Two-step cancer treatment method

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
Abraham, N.G., et al., "The Physiological Significance of Heme Oxygenase," Int. J. Biochem., 20(6):543-558 (1988).
Abraham, N.G., et al., The Physiological Significance of Heme Oxygenase, Int. J. Biochem., 20(6):543 558 (1988). *
Agarwal, A.,et al., "Gas-Generating Systems in Acute Renal Allograft Rejection in the Rat," Transplantation, 61:93-98 (1996).
Agarwal, A.,et al., Gas Generating Systems in Acute Renal Allograft Rejection in the Rat, Transplantation, 61:93 98 (1996). *
Drummond, G.S. and A. Kappas, "Preventioin of Neonatal Hyperbilirubinemia by Tin Protoporphyrin IX, a Potent Competitive Inhibitor of Heme Oxidation," Proc. Natl. Acad. Sci. USA, 78(10):6466-6470 (1981).
Drummond, G.S. and A. Kappas, Preventioin of Neonatal Hyperbilirubinemia by Tin Protoporphyrin IX, a Potent Competitive Inhibitor of Heme Oxidation, Proc. Natl. Acad. Sci. USA, 78(10):6466 6470 (1981). *
Haga, Y., et al., "Unconjugated Bilirubin Inhibits in vitro Major Histocompatibility Complex-Unrestricted Cytotoxicity of Human Lymphocytes," Biochimica et Biophysica Acta, 1316:29-34 (1996).
Haga, Y., et al., Unconjugated Bilirubin Inhibits in vitro Major Histocompatibility Complex Unrestricted Cytotoxicity of Human Lymphocytes, Biochimica et Biophysica Acta, 1316:29 34 (1996). *
Maines, M.D., "Zinc-Protoporphyrin in a Selective Inhibitor of Heme Oxygenase Activity in the Neonatal Rat," 673:339-350 (1981).
Maines, M.D., Zinc Protoporphyrin in a Selective Inhibitor of Heme Oxygenase Activity in the Neonatal Rat, 673:339 350 (1981). *
Neil, T.K., et al., "Modulation of Corneal Heme Oxygenase Expression by Oxidative Stress Agents," Journal of Ocular Pharmacology and Therapeutics, 11(3):455-468 (1995).
Neil, T.K., et al., Modulation of Corneal Heme Oxygenase Expression by Oxidative Stress Agents, Journal of Ocular Pharmacology and Therapeutics, 11(3):455 468 (1995). *
Tenhunen, R., et al., "Microsomal Heme Oxygenase: Characterization of the Enzyme," The Journal of Biological Chemistry, 244(23):6388-6394 (1969).
Tenhunen, R., et al., Microsomal Heme Oxygenase: Characterization of the Enzyme, The Journal of Biological Chemistry, 244(23):6388 6394 (1969). *
Vulapalli, S.R. and M.D. Maines, "Coordinated Expression and Mechanism of Induction of HSP32 (heme oxygenase-1) mRNA by Hyperthermia in Rat Organs," Biochimica et Biophysica Acta, 1217:273-280 (1994).
Vulapalli, S.R. and M.D. Maines, Coordinated Expression and Mechanism of Induction of HSP32 (heme oxygenase 1) mRNA by Hyperthermia in Rat Organs, Biochimica et Biophysica Acta, 1217:273 280 (1994). *
Willis, D., et al., "Heme Oxygenase: A Novel Target for the Modulation of the Inflammatory Response," Nature Medicine, 2(1):87-90 (1996).
Willis, D., et al., Heme Oxygenase: A Novel Target for the Modulation of the Inflammatory Response, Nature Medicine, 2(1):87 90 (1996). *

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US6346547B1 (en) 1999-02-08 2002-02-12 Checkpoint, Genetics, Inc. N-substituted amino acids, antioxidant pharmaceutical compositions containing n-substituted amino acids and methods for preventing cardiovascular diseases and/or preventing and/or treating antioxidant responsive diseases therewith
US20080160636A1 (en) * 2000-03-24 2008-07-03 Duke University Isolated GRP94 ligand binding domain polypeptide and nucleic acid encoding same, and screening methods employing same
US8236339B2 (en) 2001-05-15 2012-08-07 Hemocorm Limited Therapeutic delivery of carbon monoxide
US20060115542A1 (en) * 2001-05-15 2006-06-01 Motterlini Roberto A Therapeutic delivery of carbon monoxide
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US7968605B2 (en) 2002-02-04 2011-06-28 ALFAMA—Investigação e Desenvolvimento de Produtos Farmacêuticos, Lda. Methods for treating inflammatory disease by administering aldehydes and derivatives thereof
US7964220B2 (en) 2002-02-04 2011-06-21 ALFAMA—Investigação e Desenvolvimento de Produtos Farmacêuticos, Lda. Method for treating a mammal by administration of a compound having the ability to release CO
US9023402B2 (en) 2002-02-04 2015-05-05 ALFAMA—Investigação e Desenvolvimento de Produtos Farmacêuticos, Lda. Method for treating a mammal by administration of a compound having the ability to release CO
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US20110237546A1 (en) * 2002-02-04 2011-09-29 Werner Haas Method for treating a mammal by administration of a compound having the ability to release co
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US20060127501A1 (en) * 2002-11-20 2006-06-15 Motterlini Roberto A Therapeutic delivery of carbon monoxide to extracorporeal and isolated organs
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US20090149436A1 (en) * 2004-11-16 2009-06-11 Astellas Pharma Inc. Caspase inhibitor
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